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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Multiple Genes of the Renin-Angiotensin System Are Novel Targets of Wnt/<italic>β</italic>-Catenin Signaling</title><author><name sortKey="Zhou, Lili" sort="Zhou, Lili" uniqKey="Zhou L" first="Lili" last="Zhou">Lili Zhou</name><affiliation><nlm:aff wicri:cut=" and" id="aff1">Departments of Pathology</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut="; and" id="aff3">State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Li, Yingjian" sort="Li, Yingjian" uniqKey="Li Y" first="Yingjian" last="Li">Yingjian Li</name><affiliation><nlm:aff wicri:cut=" and" id="aff1">Departments of Pathology</nlm:aff></affiliation></author><author><name sortKey="Hao, Sha" sort="Hao, Sha" uniqKey="Hao S" first="Sha" last="Hao">Sha Hao</name><affiliation><nlm:aff wicri:cut=" and" id="aff1">Departments of Pathology</nlm:aff></affiliation></author><author><name sortKey="Zhou, Dong" sort="Zhou, Dong" uniqKey="Zhou D" first="Dong" last="Zhou">Dong Zhou</name><affiliation><nlm:aff wicri:cut=" and" id="aff1">Departments of Pathology</nlm:aff></affiliation></author><author><name sortKey="Tan, Roderick J" sort="Tan, Roderick J" uniqKey="Tan R" first="Roderick J." last="Tan">Roderick J. Tan</name><affiliation><nlm:aff id="aff2">Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;</nlm:aff></affiliation></author><author><name sortKey="Nie, Jing" sort="Nie, Jing" uniqKey="Nie J" first="Jing" last="Nie">Jing Nie</name><affiliation><nlm:aff wicri:cut="; and" id="aff3">State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Hou, Fan Fan" sort="Hou, Fan Fan" uniqKey="Hou F" first="Fan Fan" last="Hou">Fan Fan Hou</name><affiliation><nlm:aff wicri:cut="; and" id="aff3">State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Kahn, Michael" sort="Kahn, Michael" uniqKey="Kahn M" first="Michael" last="Kahn">Michael Kahn</name><affiliation><nlm:aff id="aff4">Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California</nlm:aff></affiliation></author><author><name sortKey="Liu, Youhua" sort="Liu, Youhua" uniqKey="Liu Y" first="Youhua" last="Liu">Youhua Liu</name><affiliation><nlm:aff wicri:cut=" and" id="aff1">Departments of Pathology</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut="; and" id="aff3">State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25012166</idno><idno type="pmc">4279741</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279741</idno><idno type="RBID">PMC:4279741</idno><idno type="doi">10.1681/ASN.2014010085</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000984</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000984</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Multiple Genes of the Renin-Angiotensin System Are Novel Targets of Wnt/<italic>β</italic>-Catenin Signaling</title><author><name sortKey="Zhou, Lili" sort="Zhou, Lili" uniqKey="Zhou L" first="Lili" last="Zhou">Lili Zhou</name><affiliation><nlm:aff wicri:cut=" and" id="aff1">Departments of Pathology</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut="; and" id="aff3">State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Li, Yingjian" sort="Li, Yingjian" uniqKey="Li Y" first="Yingjian" last="Li">Yingjian Li</name><affiliation><nlm:aff wicri:cut=" and" id="aff1">Departments of Pathology</nlm:aff></affiliation></author><author><name sortKey="Hao, Sha" sort="Hao, Sha" uniqKey="Hao S" first="Sha" last="Hao">Sha Hao</name><affiliation><nlm:aff wicri:cut=" and" id="aff1">Departments of Pathology</nlm:aff></affiliation></author><author><name sortKey="Zhou, Dong" sort="Zhou, Dong" uniqKey="Zhou D" first="Dong" last="Zhou">Dong Zhou</name><affiliation><nlm:aff wicri:cut=" and" id="aff1">Departments of Pathology</nlm:aff></affiliation></author><author><name sortKey="Tan, Roderick J" sort="Tan, Roderick J" uniqKey="Tan R" first="Roderick J." last="Tan">Roderick J. Tan</name><affiliation><nlm:aff id="aff2">Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;</nlm:aff></affiliation></author><author><name sortKey="Nie, Jing" sort="Nie, Jing" uniqKey="Nie J" first="Jing" last="Nie">Jing Nie</name><affiliation><nlm:aff wicri:cut="; and" id="aff3">State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Hou, Fan Fan" sort="Hou, Fan Fan" uniqKey="Hou F" first="Fan Fan" last="Hou">Fan Fan Hou</name><affiliation><nlm:aff wicri:cut="; and" id="aff3">State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China</nlm:aff></affiliation></author><author><name sortKey="Kahn, Michael" sort="Kahn, Michael" uniqKey="Kahn M" first="Michael" last="Kahn">Michael Kahn</name><affiliation><nlm:aff id="aff4">Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California</nlm:aff></affiliation></author><author><name sortKey="Liu, Youhua" sort="Liu, Youhua" uniqKey="Liu Y" first="Youhua" last="Liu">Youhua Liu</name><affiliation><nlm:aff wicri:cut=" and" id="aff1">Departments of Pathology</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut="; and" id="aff3">State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of the American Society of Nephrology : JASN</title><idno type="ISSN">1046-6673</idno><idno type="eISSN">1533-3450</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Activation of the renin-angiotensin system (RAS) plays an essential role in the pathogenesis of CKD and cardiovascular disease. However, current anti-RAS therapy only has limited efficacy, partly because of compensatory upregulation of renin expression. Therefore, a treatment strategy to simultaneously target multiple RAS genes is necessary to achieve greater efficacy. By bioinformatics analyses, we discovered that the promoter regions of all RAS genes contained putative T-cell factor (TCF)/lymphoid enhancer factor (LEF)-binding sites, and <italic>β</italic>-catenin induced the binding of LEF-1 to these sites in kidney tubular cells. Overexpression of either <italic>β</italic>-catenin or different Wnt ligands induced the expression of all RAS genes. Conversely, a small-molecule <italic>β</italic>-catenin inhibitor ICG-001 abolished RAS induction. In a mouse model of nephropathy induced by adriamycin, either transient therapy or late administration of ICG-001 abolished established proteinuria and kidney lesions. ICG-001 inhibited renal expression of multiple RAS genes <italic>in vivo</italic> and abolished the expression of other Wnt/<italic>β</italic>-catenin target genes. Moreover, ICG-001 therapy restored expression of nephrin, podocin, and Wilms’ tumor 1, attenuated interstitial myofibroblast activation, repressed matrix expression, and inhibited renal inflammation and fibrosis. Collectively, these studies identify all RAS genes as novel downstream targets of Wnt/<italic>β</italic>-catenin. Our results indicate that blockade of Wnt/<italic>β</italic>-catenin signaling can simultaneously repress multiple RAS genes, thereby leading to the reversal of established proteinuria and kidney injury.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Am Soc Nephrol</journal-id><journal-id journal-id-type="iso-abbrev">J. Am. Soc. Nephrol</journal-id><journal-id journal-id-type="hwp">jnephrol</journal-id><journal-id journal-id-type="pmc">jnephrol</journal-id><journal-id journal-id-type="publisher-id">ASN</journal-id><journal-title-group><journal-title>Journal of the American Society of Nephrology : JASN</journal-title></journal-title-group><issn pub-type="ppub">1046-6673</issn><issn pub-type="epub">1533-3450</issn><publisher><publisher-name>American Society of Nephrology</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25012166</article-id><article-id pub-id-type="pmc">4279741</article-id><article-id pub-id-type="publisher-id">2014010085</article-id><article-id pub-id-type="doi">10.1681/ASN.2014010085</article-id><article-categories><subj-group subj-group-type="heading"><subject>Basic Research</subject></subj-group></article-categories><title-group><article-title>Multiple Genes of the Renin-Angiotensin System Are Novel Targets of Wnt/<italic>β</italic>-Catenin Signaling</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Lili</given-names></name><xref ref-type="aff" rid="aff1">*</xref><xref ref-type="aff" rid="aff3"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Yingjian</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Hao</surname><given-names>Sha</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Dong</given-names></name><xref ref-type="aff" rid="aff1">*</xref></contrib><contrib contrib-type="author"><name><surname>Tan</surname><given-names>Roderick J.</given-names></name><xref ref-type="aff" rid="aff2"><sup>‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nie</surname><given-names>Jing</given-names></name><xref ref-type="aff" rid="aff3"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hou</surname><given-names>Fan Fan</given-names></name><xref ref-type="aff" rid="aff3"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kahn</surname><given-names>Michael</given-names></name><xref ref-type="aff" rid="aff4"><sup>§</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Liu</surname><given-names>Youhua</given-names></name><xref ref-type="aff" rid="aff1">*</xref><xref ref-type="aff" rid="aff3"><sup>†</sup></xref></contrib><aff id="aff1"><label>*</label>Departments of Pathology and</aff><aff id="aff2"><label>‡</label>Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;</aff><aff id="aff3"><label>†</label>State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and</aff><aff id="aff4"><label>§</label>Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California</aff></contrib-group><author-notes><corresp id="cor1"><bold>Correspondence:</bold> Dr. Youhua Liu, <addr-line>Department of Pathology, University of Pittsburgh School of Medicine, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261</addr-line>. Email: <email>liuy@upmc.edu</email></corresp></author-notes><pub-date pub-type="ppub"><month>1</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>10</day><month>7</month><year>2014</year></pub-date><volume>26</volume><issue>1</issue><fpage>107</fpage><lpage>120</lpage><history><date date-type="received"><day>21</day><month>1</month><year>2014</year></date><date date-type="accepted"><day>17</day><month>4</month><year>2014</year></date></history><permissions><copyright-statement>Copyright © 2015 by the American Society of Nephrology</copyright-statement><copyright-year>2015</copyright-year></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="ASN.2014010085.pdf"></self-uri><abstract><p>Activation of the renin-angiotensin system (RAS) plays an essential role in the pathogenesis of CKD and cardiovascular disease. However, current anti-RAS therapy only has limited efficacy, partly because of compensatory upregulation of renin expression. Therefore, a treatment strategy to simultaneously target multiple RAS genes is necessary to achieve greater efficacy. By bioinformatics analyses, we discovered that the promoter regions of all RAS genes contained putative T-cell factor (TCF)/lymphoid enhancer factor (LEF)-binding sites, and <italic>β</italic>-catenin induced the binding of LEF-1 to these sites in kidney tubular cells. Overexpression of either <italic>β</italic>-catenin or different Wnt ligands induced the expression of all RAS genes. Conversely, a small-molecule <italic>β</italic>-catenin inhibitor ICG-001 abolished RAS induction. In a mouse model of nephropathy induced by adriamycin, either transient therapy or late administration of ICG-001 abolished established proteinuria and kidney lesions. ICG-001 inhibited renal expression of multiple RAS genes <italic>in vivo</italic> and abolished the expression of other Wnt/<italic>β</italic>-catenin target genes. Moreover, ICG-001 therapy restored expression of nephrin, podocin, and Wilms’ tumor 1, attenuated interstitial myofibroblast activation, repressed matrix expression, and inhibited renal inflammation and fibrosis. Collectively, these studies identify all RAS genes as novel downstream targets of Wnt/<italic>β</italic>-catenin. Our results indicate that blockade of Wnt/<italic>β</italic>-catenin signaling can simultaneously repress multiple RAS genes, thereby leading to the reversal of established proteinuria and kidney injury.</p></abstract><kwd-group><kwd>renal fibrosis</kwd><kwd>CKD</kwd><kwd>renin angiotensin system</kwd><kwd>Wnt</kwd><kwd><italic>β</italic>-catenin</kwd></kwd-group><counts><page-count count="14"></page-count></counts><custom-meta-group><custom-meta><meta-name>cover-date</meta-name><meta-value>January 2015</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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